Clinical Trials /

A Phase I Study To Evaluate The Antitumor Activity And Safety Of AVX901

NCT01526473

Description:

HER2 is a protein that is over expressed in 20-30% of breast cancers. It is also found associated with lung, gastric, ovarian, and pancreatic cancers. Although there are existing therapies that can target HER2, most patients will eventually experience progression of their disease even though their cancer continues to express HER2. Therefore, new approaches are needed for treating tumors that express HER2. This clinical trial will use an investigational cancer vaccine called HER2 VRP or AVX901. The vaccine is based on a virus called Venezuelan equine encephalitis but it has been changed so it cannot cause active infection. Instead, the virus has been changed so it tells the immune system to attack cancer cells which make HER2. The objectives of the study are to evaluate the safety of immunization with HER2 VRP in patients with advanced or metastatic malignancies that express HER2, and to test whether immunization will causes a strong immune system attack against the cancer.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Breast Carcinoma
  • Esophageal Carcinoma
  • Gastric Carcinoma
  • Leukemia
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase I Study To Evaluate The Antitumor Activity And Safety Of AVX901
  • Official Title: A Phase I Study To Evaluate The Antitumor Activity And Safety Of DUKE-002-VRP(HUHER2-ECD+TM), An Alphaviral Vector Encoding The HER2 Extracellular Domain And Transmembrane Region, In Patient With Locally Advanced Or Metastatic Human Epidermal Growth Factor Receptor 2-Positive (HER2+) Cancers Including Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: Pro00034612
  • NCT ID: NCT01526473

Conditions

  • HER2+ Cancer

Interventions

DrugSynonymsArms
AVX901VRP-HER2 ECDTMAVX901

Purpose

HER2 is a protein that is over expressed in 20-30% of breast cancers. It is also found associated with lung, gastric, ovarian, and pancreatic cancers. Although there are existing therapies that can target HER2, most patients will eventually experience progression of their disease even though their cancer continues to express HER2. Therefore, new approaches are needed for treating tumors that express HER2. This clinical trial will use an investigational cancer vaccine called HER2 VRP or AVX901. The vaccine is based on a virus called Venezuelan equine encephalitis but it has been changed so it cannot cause active infection. Instead, the virus has been changed so it tells the immune system to attack cancer cells which make HER2. The objectives of the study are to evaluate the safety of immunization with HER2 VRP in patients with advanced or metastatic malignancies that express HER2, and to test whether immunization will causes a strong immune system attack against the cancer.

Detailed Description

      Metastatic breast cancer continues to account for more than 400,000 deaths yearly with HER2
      positive breast cancers representing approximately one third of cases. Despite the efficacy
      of trastuzumab in HER2 overexpressing breast cancer, progression of metastatic disease is
      inevitable. Lapatinib, when combined with capecitabine, improves time to progression in those
      with trastuzumab resistant disease, but lapatinib resistance also develops in the majority of
      these patients. HER2 overexpression is also reported in lung, gastric, ovarian, and
      pancreatic cancers, all of which are also in need of improved treatment options. Because HER2
      continues to be expressed in patients with refractory disease, using an immune-targeting
      approach against HER2 remains a promising strategy. A number of clinical trials have
      confirmed the ability of vaccines to activate T cell and antibody responses against HER2. We
      propose using a propagation-defective, single-cycle, RNA replicon vector system that
      expresses HER2 as an antigen-specific cancer vaccine in a Phase I clinical trial in patients
      with advanced or metastatic malignancies expressing HER2. The vaccine was prepared from an
      attenuated strain of an alphavirus in which 3 of the 7 viral genes were removed and replaced
      with a HER2 gene to create a self-amplifying RNA (replicon) that expresses large amounts of
      HER2. The HER2 gene used includes the extracellular domain (ECD) and transmembrane (TM)
      regions of HER2 but not the ICD region. The HER2 ECDTM replicon is packaged into virus-like
      replicon particles (VRP) by providing the alphavirus structural proteins from separate RNA
      molecules. When VRP are used for immunization, the VRP infect individual cells and the
      replicon expresses HER2 which then induces an immune response.

      The primary objective of the study is to evaluate the safety of immunization with HER2 ECDTM
      VRP in patients with advanced or metastatic HER2-expressing malignancies. The study will also
      monitor immune responses to HER2. Preliminary data on tumor response rate will also be
      collected.
    

Trial Arms

NameTypeDescriptionInterventions
AVX901ExperimentalAVX901 at 4 x 108 IU intramuscularly, given every 2 weeks for a total of three doses.

    Eligibility Criteria

            Inclusion criteria
    
              -  One of the following subgroups of patients with HER2 overexpression as follows:
    
                 (i) Histologically-confirmed breast cancer that is metastatic or locally recurrent
                 (7th Edition of the AJCC TNM System) and measurable and/or evaluable or non-measurable
                 by RECIST 1.1 criteria with HER2/neu overexpression by immunohistochemistry (2+,3+) or
                 FISH+ and progressive disease despite having received at least 1 prior FDA approved
                 HER2 targeted (e.g. trastuzumab, trastuzumab plus pertuzumab, T-DM1, or lapatinib)
                 (determined by their physician).*
    
                 *Prior therapy has at least one of the following stipulations:
    
              -  Patients may have received neoadjuvant or adjuvant treatment with prior trastuzumab or
                 lapatinib treatment
    
              -  Patients have received a a trastuzumab, trastuzumab + pertuzumab, or T-DM1-based
                 therapy for locally advanced or metastatic disease for a minimum of 9 weeks duration.
                 Patients may have received more than 1 trastuzumab-based combination therapy.
    
              -  Patients have received a lapatinib-based therapy for locally advanced or metastatic
                 disease for a minimum of 9 weeks duration. Patients may have received more than 1
                 lapatinib-based combination therapy.
    
            (ii) Histologically-confirmed gastric, esophageal, or gastroesophageal adenocarcinoma that
            is metastatic or locally recurrent (7th Edition of the AJCC TNM System) and measurable or
            non-measurable by RECIST 1.1 criteria with HER2/neu overexpression by immunohistochemistry
            (2+,3+) or FISH+ and progressive disease despite having received at least 1 prior HER2
            targeted therapy for a minimum of 9 weeks duration) (determined by their physician). or
            with previously documented HER2 over-expressing disease not being currently treated on a
            HER2 targeted therapy.
    
            (iii) Other histologically confirmed metastatic (stage IV) or locally recurrent (stage III)
            (7th Edition of the AJCC TNM System) malignancy with HER2/neu overexpression by
            immunohistochemistry (2+,3+) or FISH+. Because there are no other malignancies with FDA
            approved HER2 targeting therapies, no prior HER2 directed therapy will be required for this
            subgroup. However, patients will have been required to have at least 1 line of therapy with
            a known survival benefit for their malignancy.
    
              -  Adults at least 18 years of age at the time of signing the Informed Consent Form;
    
              -  Written informed consent obtained from the patient prior to performing any
                 study-related procedures, including screening visits. however, CT scans, bone scans,
                 MUGA, Echocardiogram, EKG,and labs performed as standard of care prior to signing
                 consent can be used to fulfill eligibility requirements if they were performed within
                 8 weeks of the first dose of AVX901 (for the MUGA or echocardiogram) and within 4
                 weeksof the first dose of study drug for the remainder of the studies
    
              -  Resolution of all toxic side effects of prior chemotherapy, radiotherapy or surgical
                 procedures to NCI CTCAE (version 4.03) Grade ≤ 1 (with the exception of grade 2
                 alopecia, grade 2 neuropathy and grade 2 fatigue);
    
              -  Karnofsky performance status greater than or equal to 80% or ECOG status of 0 or 1 ;
    
              -  Adequate hematologic function: (WBC = 2500 mm3, hemoglobin > 10 mg/dl, platelets >
                 100,000/mm3);
    
              -  Adequate renal and hepatic function (Cr < 2.0 mg/dl; bilirubin < 2 X ULN; AST < 2.5 x
                 ULN, ALT < 2.5 X ULN);
    
              -  Normal cardiac function defined as either a MUGA or ECHO with LVEF in normal
                 institutional range (MUGA 50%; ECHO 55%);
    
              -  Female patients must be of non child-bearing potential or use effective contraception,
                 e.g., use of oral contraceptives with an additional barrier method (since the study
                 drug may impair the effectiveness of oral contraceptives), double barrier methods
                 (diaphragm with spermicidal gel or condoms with contraceptive foam), Depo-Provera,
                 partner vasectomy, total abstinence, and willing to continue the effective
                 contraception method for 30 days after the last dose of AVX901;
    
              -  Ability to return to Duke University Medical Center for adequate follow-up as required
                 by this protocol;
    
              -  Current therapy with endocrine agents (tamoxifen, raloxifene, torimifene and all
                 aromatase inhibitors) and/or bisphosphonates and/or RANK-ligand inhibitors is
                 permitted.
    
            Exclusion criteria
    
              -  Except for patients on the concurrent HER2 targeted therapy (cohort 2) cohort,
                 patients may not receive cytotoxic chemotherapy, monoclonal antibodies (other than
                 RANK-ligand inhibitors being used for bone protection), HER2 targeted therapy such as
                 lapatinib, or radiation therapy in the 3 weeks before the first injection, during the
                 injection period or for at least 2 weeks after the last injection. Patients may have
                 received prior radiation including for brain metastases.
    
              -  History of auto-immune disease such as, but not restricted to, inflammatory bowel
                 disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, or
                 multiple sclerosis. Prior history of autoimmune thyroiditis or vitiligo is permitted.
    
              -  Serious chronic or acute illness considered by the P.I. to constitute an unwarranted
                 high risk for investigational drug treatment.
    
              -  Medical or psychological impediment to probable compliance with the protocol.
    
              -  Concurrent or prior second malignancy (within the past 5 years) other than
                 non-melanoma skin cancer, controlled superficial bladder cancer or controlled cervical
                 cancer.
    
              -  Presence of active infection or systemic use of antimicrobials within 72 hours prior
                 to the first injection
    
              -  Patients on steroid therapy (or other immunosuppressives such as azathioprine or
                 cyclosporine A) are excluded on the basis of potential immune suppression. Patients
                 must have had 6 weeks of discontinuation of any steroid therapy prior to enrollment
                 (except steroids used as anti-emetics for systemic chemotherapy which are permitted).
    
              -  Presence of an active acute or chronic infection including HIV (as determined by ELISA
                 and confirmed by Western Blot) or viral hepatitis (as determined by HBsAg and
                 Hepatitis C serology). Patients with HIV are excluded based on immuno-suppression,
                 which may render them unable to respond to the vaccine; patients with chronic
                 hepatitis are excluded because of concern that hepatitis could be exacerbated by the
                 injections. .
    
              -  Pregnant or nursing women
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Safety
    Time Frame:3 months
    Safety Issue:
    Description:The primary objective of the study is to evaluate the safety of immunization with HER2 ECDTM VRP in patients with advanced or metastatic HER2-expressing malignancies

    Secondary Outcome Measures

    Measure:Immune response
    Time Frame:3 months
    Safety Issue:
    Description:The secondary objective of the study HER2 specific response by ELISPOT and ELISA.

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Active, not recruiting
    Lead Sponsor:H. Kim Lyerly

    Trial Keywords

    • Alphavirus
    • Vaccine
    • Immunotherapy
    • HER2

    Last Updated

    March 23, 2017